Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action

Abstract

Diabetes is a group of metabolic disorders with an increased risk of developing cognitive impairment and dementia. The hippocampus in the forebrain contains an abundance of insulin receptors related to cognitive function and plays an important role in the pathophysiology of neurodegenerative disorders. Berberine from traditional Chinese medicine has been used to treat diabetes and diabetic cognitive impairment, although its related mechanisms are largely unknown. In this study, a STZ diabetes rat model feeding with a high-fat diet was used to test the effects of berberine compared with metformin. Oral glucose tolerance and hyperinsulinemic-euglycemic clamp were used for glucose metabolism and insulin resistance. The Morris water maze was used to observe the compound effects on cognitive impairment. Serum and hippocampal [Formula: see text]-amyloid peptide (A[Formula: see text], Tau and phosphorylated Tau protein deposition in the hippocampi were measured. The TUNEL assay was used to detect the neuronal apoptosis, supported by histomorphological changes and transmissional electron microscopy (TEM) image. Our data showed that the diabetic rats had a significantly cognitive impairment. In addition to improving glucose metabolism and reducing insulin resistance, berberine significantly improved the cognitive function in the rat. Berberine also effectively decreased the expression of hippocampal tau protein, phosphorylated Tau, and increased insulin receptor antibodies. Moreover, berberine downregulated the abnormal phosphorylation of A[Formula: see text] and Tau protein and improved hippocampal insulin signaling. The TUNEL assay confirmed that berberine reduced hippocampal neuronal apoptosis supported by TEM. Thus, berberine significantly improved the cognitive function in diabetic rats by changing the peripheral and central insulin resistance. The reduction of neuronal injury, A[Formula: see text] deposition, abnormal phosphorylation of Tau protein, and neuronal apoptosis in the hippocampus were observed as the related mechanisms of action.

Neuroprotective Effect and Possible Mechanisms of Berberine in Diabetes-Related Cognitive Impairment: A Systematic Review and Meta-Analysis of Animal Studies

“…In the 20 included studies, 13 studies were published in English ( Bhutada et al, 2011 ; Kalalian-Moghaddam et al, 2013 ; Moghaddam et al, 2013 ; Moghaddam et al, 2014 ; Zhou et al, 2016 ; Chen et al, 2017 ; Li et al, 2018 ; Wang et al, 2018 ; Wang et al, 2019 ; Adefegha et al, 2021 ; Tian et al, 2021 ; Wu et al, 2021 ; Zhang et al, 2021 ) and 7 studies were published in Chinese ( Ma et al, 2012a ; Ma et al, 2012b ; Tong et al, 2019 ; Cao et al, 2021 ; Liu, 2021 ; Ma and Liu, 2021 ; Xuan, 2021 ). A total of 442 diabetic model animals were enrolled, including 278 in the treatment group and 164 in the control group.…”

“…In the preparation of diabetes models, seven studies established animal models by intraperitoneal injection of streptozotocin (STZ) only, and the dose range for STZ injections was 40–60 mg/kg ( Bhutada et al, 2011 ; Kalalian-Moghaddam et al, 2013 ; Moghaddam et al, 2013 ; Moghaddam et al, 2014 ; Tong et al, 2019 ; Adefegha et al, 2021 ; Ma and Liu, 2021 ). Six studies were to induced diabetes models by intraperitoneal injection of STZ combined with a high-sugar and high-fat diet (HSFD) or high-fat diet (HFD), and the dose range of STZ was 30–50 mg/kg ( Ma et al, 2012a ; Ma et al, 2012b ; Zhou et al, 2016 ; Liu, 2021 ; Xuan, 2021 ; Zhang et al, 2021 ). Five studies were to induce diabetes models by caudal vein injection of STZ (25 mg/kg) combined with HSFD or HFD ( Chen et al, 2017 ; Wang et al, 2018 ; Wang et al, 2019 ; Tian et al, 2021 ; Wu et al, 2021 ).…”

“…The maximum duration of administration was 23 weeks (range, 2–23 weeks), and the maximum dose of berberine was 200 mg/kg/d (range, 20–200 mg/kg/d). In order to assess the effect of berberine on blood glucose in diabetic models, 15 studies recorded the FBG level ( Bhutada et al, 2011 ; Ma et al, 2012a ; Ma et al, 2012b ; Kalalian-Moghaddam et al, 2013 ; Moghaddam et al, 2013 ; Moghaddam et al, 2014 ; Zhou et al, 2016 ; Wang et al, 2018 ; Tong et al, 2019 ; Wang et al, 2019 ; Adefegha et al, 2021 ; Cao et al, 2021 ; Liu, 2021 ; Tian et al, 2021 ; Xuan, 2021 ), 3 studies recorded serum insulin ( Li et al, 2018 ; Wang et al, 2018 ; Wang et al, 2019 ), 3 studies recorded the OGTT level ( Wang et al, 2019 ; Cao et al, 2021 ; Zhang et al, 2021 ), 2 studies recorded the ITT level ( Li et al, 2018 ; Cao et al, 2021 ), and 1 study recorded the HbA1c level ( Zhou et al, 2016 ). Behavioral tests were used to evaluate the learning and memory function of animals.…”

“…Behavioral tests were used to evaluate the learning and memory function of animals. For further assessment of the neuroprotective effect of berberine on DCI model animals, 14 studies conducted the MWM test ( Bhutada et al, 2011 ; Ma et al, 2012b ; Zhou et al, 2016 ; Li et al, 2018 ; Wang et al, 2018 ; Tong et al, 2019 ; Wang et al, 2019 ; Cao et al, 2021 ; Liu, 2021 ; Ma and Liu, 2021 ; Tian et al, 2021 ; Wu et al, 2021 ; Xuan, 2021 ; Zhang et al, 2021 ), 2 studies conducted the Y-maze test ( Kalalian-Moghaddam et al, 2013 ; Li et al, 2018 ), 2 studies conducted the conditioned fear test ( Chen et al, 2017 ; Li et al, 2018 ), and 1 study conducted the passive avoidance test ( Kalalian-Moghaddam et al, 2013 ). Detailed information on berberine in each study is displayed in Table 1 .…”

9-O-Terpenyl-Substituted Berberrubine Derivatives Suppress Tumor Migration and Increase Anti-Human Non-Small-Cell Lung Cancer Activity

“…Berberine not only contributes to cancer therapy but also has reported benefits in the treatment of inflammation, diabetes, and pathogenic infection and can attenuate acute renal injury and neurodegenerative diseases [34][35][36][37][38][39]. We synthesized B4 and B5 from berberrubine, derived from berberine; both B4 and B5 exert higher anti-NSCLC activities than berberine and berberrubine.…”